Voss Examines TKI/IO and IO/IO Regimens in Non–Clear Cell RCC

Martin Voss, MD

Clinical Director, Genitourinary Medical Oncology Service

Memorial Sloan Kettering Cancer Center

New York, NY

CASE SUMMARY

• A 57-year-old man presents to the emergency department with new-onset gross hematuria, right flank pain, and weight loss.

Medical history

• Hypertension, well controlled on daily angiotensin-converting enzyme inhibitor
• No history of malignancy
  

Social history

• Employed as a bank teller
• Nonsmoker
  

Family history

• Father died of colon cancer at 60, mother underwent hysterectomy for uterine fibroids at age 37; no other family history of malignancy

Diagnostic workup

• Abdominal CT: 7-cm solid mass in right kidney; liver and lung metastases detected
• Laboratory test results: normal complete blood count (CBC) plus differential and comprehensive metabolic panel
• Histopathology: core needle biopsy – papillary architecture consistent with non–clear cell renal cell carcinoma (nccRCC)
• Molecular testing results: awaiting results

Peers & Perspectives in Oncology: What data support the use of lenvatinib (Lenvima) plus pembrolizumab (Keytruda) for this patient?

VOSS: The KEYNOTE-B61 study [NCT04704219]…is a study that is large for nccRCC trials. It’s a single-arm phase 2 study that enrolled patients with advanced, metastatic, or unresectable nccRCC with no prior systemic therapy. Patients with chromophobe, papillary, unclassified, or translocation RCC were allowed…. One hundred fifty-eight patients were enrolled across 14 countries…and patients received standard lenvatinib/pembrolizumab at the same schedule that we are using in ccRCC based on the CLEAR data [NCT02811861].¹

Patients were treated for up to 2 years with pembrolizumab and open-ended lenvatinib with tumor assessments every 3 months. The primary end point here was objective response rate [ORR]. The majority of patients had papillary RCC.

These are the follow-up data after the second interim analysis presented in 2024.¹ Across the entire population, the ORR was 50%. There were complete responses [CRs], and the primary progression rate was quite low, which I always feel is important as we consider trials for clinical decisions in our practices.

[Looking at] response rate by histology, there were 93 patients with papillary RCC. These numbers are robust [enough] to demonstrate an ORR of over 50% and an almost 11% CR rate in papillary kidney cancer [Figure¹]. This is comparable to what we achieve in ccRCC. If you look at chromophobe, unclassified, translocation, and [other], there is activity for all subtypes. It is notable that some of these are small. For translocation, there’s a 66% ORR, but it’s only 6 patients; the 16% CR rate was a single patient who had a CR. It’s relevant to note that a patient with translocation RCC was able to achieve a CR, but you can’t put too much emphasis on the percentages.

In the era of TKI [tyrosine kinase inhibitor] monotherapy, the chromophobe subtype stood out as patients who responded equally well to systemic therapy as ccRCC. With mTOR inhibitors we used to see better efficacy with chromophobes, but in the era of immune checkpoint inhibitor therapy, the chromophobes have disappointed a little bit. For all these data sets we see similar findings. There is some efficacy, but it’s always the least of the subgroups. In chromophobe RCC you don’t typically see CRs. We see an ORR of 34%, which is pretty good, but most RCC experts think it’s mostly driven by the lenvatinib.

The vast majority of patients achieve some degree of tumor shrinkage; even the ones who don’t achieve a partial response seemed to have benefit here. The median duration of response was 19.5 months across all the patients.² Given the small size, it’s probably not as good as what we are used to seeing with ccRCC, but it speaks to this generally being active, and for many patients, being active with durable effect.

Progression-free survival [PFS] and overall survival [OS] were secondary end points on this trial, and with 23 months’ median follow-up, [we reported on PFS in] the total population, the papillary subgroup, and chromophobe as the second-largest subgroup.¹ The chromophobe subgroup is quite small; there are only 13 PFS events, but, nonetheless, you see that the median PFS is in the range of 15 to 20 months for these patients. Despite having a lesser response to therapy, patients with chromophobe RCC still have PFS data that look good. That’s probably because they represent more indolent chromophobe cases and indolent papillary cases. All of this together says it’s an active regimen for response, duration, PFS, and so forth.

Adverse events were not different from what we’re used to seeing.² At the time that KEYNOTE-B61 was conducted and when it was reported, all of us had been using TKI plus IO [immunotherapy] regimens sufficiently, so there were no new safety signals. Approximately 20% of patients discontinued therapy due to toxicity. About 14% of patients required corticosteroids for toxicity management. The day-to-day toxicity is driven by the TKI more than the PD-1 inhibitor. There was no [significant] hepatotoxicity.

How was cabozantinib (Cabometyx) plus nivolumab (Opdivo) studied in this setting?

This was a much smaller study conducted by our group at Memorial Sloan Kettering Cancer Center.³ This was a single-center investigator-initiated trial [NCT03635892] that reported long before the KEYNOTE-B61 study. This [looked at] cabozantinib/nivolumab, motivated by the good data seen in ccRCC in the CheckMate 9ER study [NCT03141177]. This was a trial very similar in design [but] much smaller [than KEYNOTE-B61]. [Patients had to have] unresectable or metastatic disease and no prior treatment, but there was a subgroup of patients who could have had 1 prior line of therapy.

When we set up this trial, we set it up in 2 cohorts—1 cohort being papillary, unclassified, or translocation RCC, and then a separate cohort designed for chromophobe RCC, anticipating that there might be less of an efficacy signal, because we had seen several times before that IO seemed to have less activity in chromophobe RCC. That second cohort closed early because although there was tumor shrinkage on the waterfall plots, there was no patient who achieved an objective response at the first interim analysis of treating 7 patients.

The primary end point here was also ORR. The dosing schedule was a standard cabozantinib/nivolumab dosing schedule with dose-attenuated cabozantinib starting at 40 mg, the way we do it for the FDA label in ccRCC. [There were 26 treatment-naive] patients on the trial [and 14] patients who had had 1 prior line. They were all IO naive, so patients in the second-line [setting] had been pretreated with a TKI.

What were the outcomes of this trial?

The ORR for first-line patients was 54%, very reminiscent of what we saw with lenvatinib/pembrolizumab. There were some patients with CRs, and the primary progression rate was quite low. No one in the first-line setting had primary progressive disease, and few patients with pretreated nccRCC [had progressive disease]. The biggest subgroup was patients with papillary RCC, [showing] an ORR of almost 50% with some CRs seen…. It was a similar story to what we saw for the lenvatinib/pembrolizumab combination. [There were] small numbers for unclassified and translocation RCC; nonetheless, responses were seen, so that matters.

[Looking at the] waterfall plot, [it has] much smaller numbers than what we saw before, but the vast majority of patients respond. There are some deep responses and a few patients who have primary progression. There were several patients with lasting response, and the median duration of response for so small a sample size is a less meaningful number but was very similar to what we saw with lenvatinib/pembrolizumab.

Median PFS was 13 months, and median OS was 28 months. Remember that this is a mix of patients with first-line and second-line [therapy]. The numbers are quite small, but overall, the story is similar [for PFS by subgroup].

Again, we didn’t see any adverse [toxicity] signal here for the nccRCC variants. Neither trial had any deaths [due to] toxicity, and the discontinuation rates were similar to what we are used to seeing in other cohorts treated with these regimens.

What role does lenvatinib plus everolimus have in nccRCC?

This is the VEGF TKI/mTOR inhibitor combination; this has been on the market for some time. The combination was originally approved for ccRCC in 2015 based on [data from] a phase 2 randomized trial. That original trial that led to its FDA approval did not include any patients with nccRCC, but subsequently, there was a small study [whose findings were] published in European Urology in 2021 that treated patients across different variants in the first-line setting with the combination of lenvatinib/everolimus.⁴ This was an industry-run multicenter study conducted across continents, but it was a small trial with 31 patients in total, and it established that there is efficacy for this combination.

This is a different study, so we can’t compare them head-to-head, but the efficacy signal for papillary is more in keeping with what we used to see before we had IO combinations. It’s an ORR of 15% with no CRs. Across the trial, there were no CRs. It’s a 31-patient trial, [so] we have to take it with a grain of salt, but this is a different feel from TKI/IO combinations. This is an older trial whose [findings] were already reported prior to these other studies. It speaks to the fact that this combination can work, but most would not use it in the first-line setting unless someone had a contraindication to IO. Patients with chromophobe RCC tend to not respond so well to PD-1–directed agents, [but] they had a 44% ORR [with lenvatinib/ everolimus]. I always point to the fact that it was 9 patients. This always comes up [supporting] lenvatinib/everolimus for chromophobe RCC, and clearly there is activity, but we’re limited by numbers here. The median PFS is in the 9- to 13-month range [for] first-line data.

What data were presented on the combination of ipilimumab (Yervoy) and nivolumab?

Ipilimumab plus nivolumab had been studied previously by a phase 2 study called the CHECKMATE 920 study [NCT02982954]…. CHECKMATE 920...was a single-arm study that tested ipilimumab/nivolumab across a number of unusual scenarios: nccRCC, brain metastases, patients with impaired renal function, and so forth, and gave the sense that there were some patients who had good benefit. Recently, at the 2024 European Society for Medical Oncology Annual Congress, European investigators reported on a randomized trial [SUNNIFORECAST; NCT03075423] that was mostly conducted in Germany and France….

[Investigators enrolled] patients with untreated metastatic nccRCC, [including] papillary, chromophobe, collecting duct, medullary, unclassified, and pure sarcomatoid variants. They all had to have measurable disease, and they were randomly assigned to receive either ipilimumab/nivolumab on a standard schedule [with ipilimumab given] 4 times using RCC dosage, followed by nivolumab maintenance every 2 weeks or monthly, vs [standard of care (SOC)]. It’s an interesting design. Patients could be treated with ipilimumab/nivolumab or with anything that the medical oncologist wanted to give instead, be that TKI monotherapy, TKI/IO, or even an mTOR inhibitor.

It was a sizable study; over 300 patients were randomly assigned, and the randomization was stratified appropriately by papillary vs nonpapillary, and that was based on the fact that in the CHECKMATE 920 study, the clearest signal for efficacy was in papillary RCC.⁵ It was not quite clear how well other variants might respond. There was central pathological review. This is a well-designed study with robust design, and the primary end point was a landmark analysis of OS at 12 months. That was much discussed when the data were presented, and the authors argued that they chose that landmark end point so that they would have sufficient events to run the study and not too large a size and get results sooner rather than later.

They met their primary end point of OS at 12 months. It was a positive study [whose findings] demonstrated significantly better 12-month OS with ipilimumab/nivolumab [than the] SOC [86.9% vs 76.8%, respectively]. I think the largest proportion of these patients [received] single-agent TKI based on this being conducted in Europe, where it’s not always so easy to get combination regimens approved through patients’ insurance.

There is the sense that most patients here seem to benefit more from ipilimumab/nivolumab. There’s the question of whether PD-L1 status mattered or not. The signal is toward less benefit for the nonexpressing patients. I think that is hypothesis generating, [but] I don’t know that you can pull a biomarker signal out of this.

I think it’s very important for us to look at the ORR and the CR rates. If we look at the various entities, those with papillary RCC had an ORR of [over] 30% and a 10% CR rate. There was clear efficacy here, and again, the [patients with] chromophobe RCC stand out to have a little bit less…efficacy. Nonetheless, one-fourth of the patients had partial responses with no CRs.

DISCLOSURE: Voss previously reported consulting or advisory roles with Affimed N.V., AVEO Oncology, Eisai, Exelixis, Genentech, Merck, MicuRx Pharmaceuticals, and Oncorena.

REFERENCES:

1. Voss MH, Gurney H, Atduev V, et al. First-line pembrolizumab plus lenvatinib for non–clear cell renal carcinomas (nccRCC): extended follow-up of the phase 2 KEYNOTE-B61 study. J Clin Oncol. 2024;42(suppl 4):2. doi:10.1200/JCO.2024.42.4_suppl.2

2. Albiges L, Gurney H, Atduev V, et al. Pembrolizumab plus lenvatinib as first-line therapy for advanced non-clear-cell renal cell carcinoma (KEYNOTE-B61): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 2023;24(8):881-891. doi:10.1016/S1470-2045(23)00276-0

3. Fitzgerald KN, Lee CH, Voss MH, et al. Cabozantinib plus nivolumab in patients with non-clear cell renal cell carcinoma: updated results from a phase 2 trial. Eur Urol. 2024;86(2):90-94. doi:10.1016/j.eururo.2024.04.025

4. Hutson TE, Michaelson MD, Kuzel TM, et al. A Single-arm, multicenter, phase 2 study of lenvatinib plus everolimus in patients with advanced non-clear cell renal cell carcinoma. Eur Urol. 2021;80(2):162-170. doi:10.1016/j.eururo.2021.03.015

5. Bergmann L, Ahrens M, Albiges L, et al. Prospective randomised phase-II trial of ipilimumab/nivolumab versus standard of care in non-clear cell renal cell cancer: results of the SUNNIFORECAST trial. Ann Oncol. 2024;35(suppl 2):S1263. doi:10.1016/j.annonc1623